tbuckley/cabot-search huggingface dataset:
Abstract 1915: Addressing cancer health disparities among US minority populations with patient-derived xenografts
Authors: Brian J. Sanderson, Paul Lott, Anuj Srivastava, Jeffrey H. Chuang, Luis G. Carvajal-Carmona
Journal: Cancer Research (2022)

Abstract Despite the tremendous advances in cancer prevention and treatment strategies that have been achieved since the war on cancer plan in the 1970’s, it is clear that not all communities are equally benefiting from such advances and that minority populations nearly always have worse cancer health outcomes. These cancer health disparities are the result of complex interactions between social determinants of health, population-specific cultural behaviors and lifestyles, and unique biological differences that associate with ancestry. Two major limitations to the advancement of precision medicine in minority groups include the lack of: i) race/ethnic appropriate genomic data, which will facilitate identifying priority targets for therapeutic development, and ii) patient-derived models, such as patient-derived xenografts (PDXs) that recapitulate the unique interactions of germline and somatic genetics that exist in minority patients. In this presentation we describe the development of an analytical pipeline to quantify continental genetic ancestry that we have developed for the Cancer Genomics Cloud as part of the PDX Development and Trials Center Research Network (PDXnet). This pipeline leverages a novel reference panel for the program SNPweights, which includes a greater representation of genomic data from Native and Latin American populations than previously published reference panels, and thus provides improved assignment of American continental ancestry. We use this pipeline to characterize the diversity of the PDX models in PDXnet, which represent a manifold increase in models with African and American continental genetic ancestry compared with those available in other public resources. Finally, we present power analyses to demonstrate that additional PDX models derived from patients from minority populations are critically needed to effectively address health equity goals in the US. Citation Format: Brian J. Sanderson, Paul Lott, Anuj Srivastava, PDXNet Consortium, Jeffrey H. Chuang, Luis G. Carvajal-Carmona. Addressing cancer health disparities among US minority populations with patient-derived xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1915.
Abstract 387: Blood brain barrier (BBB) disruption by tumor treating fields (TTFields) in a human 3D <i>in vitro</i> model
Authors: Ellaine Salvador, Almuth F. Kessler, Theresa Köppl, Sebastian Schönhärl, Malgorzata Burek, Catherine Tempel Brami, Tali Voloshin, Moshe Giladi, Ralf-Ingo Ernestus, Mario Löhr, Carola Y. Förster, Carsten Hagemann
Journal: Cancer Research (2022)

Abstract The clinical translatability of novel drug delivery systems begins with basic scientific breakthroughs. Our recent discovery of the ability of Tumor Treating Fields (TTFields) to potentially and transiently disrupt the blood brain barrier (BBB) using our murine in vitro and in vivo models, led us to validate our findings in a human 3D in vitro model established in our lab. The model consists of primary brain microvascular endothelial cells co-cultured with immortalized perciytes in a transwell system. TTFields are alternating electric fields of low intensity (1-3V/cm) and intermediate frequency (100-300kHz), which are effective and approved for the treatment of glioblastoma (GBM) using 200kHz frequency. Our murine data point out that TTFields could disrupt the BBB optimally at 100kHz. To investigate if TTFields exhibit similar effects in the human cell-based in vitro model, it was subjected to TTFields at various frequencies for 24-96h. Cells were afterwards made to recover for 24-96h. To assess BBB integrity and compromise, transendothelial electrical resistance (TEER) was measured before start of TTFields, immediately after end of TTFields, as well as 24-96h after TTFields. In addition, a permeability assay was performed. Finally, immunofluorescence (IF) staining visualized the effects of TTFields on tight junction protein claudin-5 localization. TTFields application of all investigated frequencies significantly decreased TEER. However, the strongest effects were observed with 100kHz after 72h. IF staining revealed delocalization of claudin-5 from the cell boundaries to the cytoplasm. Restoration of cell integrity was already evident as early as 24h, with complete recovery after 48h. Results using our human 3D in vitro model validated our previous observations from murine in vitro and in vivo models that TTFields could transiently disrupt the BBB. These findings provide fundamental pre-clinical data for translation from bench to bedside. Accordingly, TTFields demonstrate to be a promising novel approach in opening the BBB to facilitate drug delivery for improved treatment of central nervous system diseases including devastating brain tumors such as GBM. Citation Format: Ellaine Salvador, Almuth F. Kessler, Theresa Köppl, Sebastian Schönhärl, Malgorzata Burek, Catherine Tempel Brami, Tali Voloshin, Moshe Giladi, Ralf-Ingo Ernestus, Mario Löhr, Carola Y. Förster, Carsten Hagemann. Blood brain barrier (BBB) disruption by tumor treating fields (TTFields) in a human 3D in vitro model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 387.
Abstract 1833: Tumor treating fields induce DNA damage and apoptosis in medulloblastoma
Authors: Ryan T. Nitta, Gordon Li
Journal: Cancer Research (2022)

Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children and accounts for approximately 20% of all pediatric central nervous system tumors. Current multimodal treatment has led to a 70-90% five-year overall survival rate, however, the prognosis for patients with tumor dissemination and recurrent MB remains poor. Additionally, the majority of survivors exhibit long-term neurocognitive and neuroendocrine complications because of the cytotoxic drugs and high dose radiation. Consequently, more effective and less toxic treatments are necessary in order to raise the quality of life for these young patients. Tumor Treating Fields (TTFields) are an exciting new therapeutic opportunity for MB. TTFields are low intensity, alternating electric fields that disrupt cell division through physical interactions with key molecules during mitosis. The side effects from TTFields treatments are incredibly low, making it an ideal candidate for MB therapy. Currently TTFields were found to increase the survival of adult brain tumor patients by dysregulating the cytoskeletal network leading to mitotic arrest as well as other varied multi-modal mechanisms of action. To determine if TTFields can be an effective treatment for MB, we conducted an in vitro study treating multiple MB cell lines with TTFields. We discovered that TTFields treatment reduced cell growth in three different MB molecular subgroups (SHH, Group 3, and Group 4) with an optimal frequency of 200-300 kHz. We also observed that TTFields treatment dysregulated actin polymerization that corresponded with a reduction in cell motility and invasion. TTFields treatment also increased DNA damage (γH2AX, 53BP1) that correlated with an increase in apoptotic cells. To expand on these initial findings, we conducted a combinatorial study with the small molecule inhibitor, CX-4945. CX-4945 is an inhibitor to casein kinase 2 and is currently being used in a phase I clinical trial to treat recurrent MB (NCT03904862). We discovered that CX-4945 enhanced the growth reduction of TTFields treatment. In addition, combining CX-4945 and TTFields increased the number of cells with dysregulated actin which correlated with a decrease in MB migration and invasion. Our findings demonstrate that TTFields may be a novel and less toxic method to treat MB patients. Citation Format: Ryan T. Nitta, Gordon Li. Tumor treating fields induce DNA damage and apoptosis in medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1833.
Assessment of Physical Activity and Healthy Eating Behaviors Among US Adults Receiving Bariatric Surgery
Authors: Young-Rock Hong, Sandhya Yadav, Ryan Suk, Alexandra M. Lee, Faith A. Newsome, Crystal N. Johnson-Mann, Michelle I. Cardel, Kathryn M. Ross
Journal: JAMA Network Open (2022)

Bariatric surgery effectively treats severe obesity and metabolic diseases. However, individual outcomes vary depending on sustainable lifestyle change. Little is known about lifestyle patterns after bariatric surgery among the US population.To compare the level of physical activity and eating behavior among postbariatric surgery patients, individuals eligible for surgery, and those with normal weight.A cross-sectional study using nationally representative survey data from National Health and Nutrition Examination Survey 2015-2018. Respondents included for analysis were age 18 years or older, and categorized by individuals with normal weight, individuals who received bariatric surgery, and individuals clinically eligible for bariatric surgery. Analyses were performed from February to October 2021.Self-reported measures were used to assess physical activity (moderate-to-vigorous physical activity [MVPA], sedentary activity, and whether PA guidelines were met) and eating behaviors (total energy intake and Healthy Eating Index [HEI]-2015 diet quality scores).Of 4659 study participants (mean [SD] age, 46.1 [18.6] years; 2638 [weighted percentage, 58.8%] women; 1114 [weighted percentage, 12.7%] Black, 1570 [weighted percentage, 68.6%] White), 132 (3.7%) reported that they had undergone any bariatric surgery. Median (IQR) time since surgery was 7 (3-10) years. After propensity-score weighting, individuals who underwent bariatric surgery reported more time spent in MVPA than those eligible for surgery (147.9 min/wk vs 97.4 min/wk). Among respondents with normal weight, 45.6% (95% CI, 40.8% to 52.4%) reported meeting PA guidelines, almost 2 times higher than those in the bariatric surgery (23.1%; 95% CI, 13.8% to 32.4%) or in the surgery-eligible group (20.3%; 95% CI, 15.6% to 25.1%). Propensity-score weighted overall HEI was higher for individuals with normal weight (54.4; 95% CI, 53.0 to 55.9) than those who underwent bariatric surgery (50.0; 95% CI, 47.2 to 52.9) or were eligible for the surgery (48.0; 95% CI, 46.0 to 50.0). Across all HEI components, mean scores were similar between the bariatric surgery and surgery-eligible groups. Total energy intake was the lowest among those who underwent bariatric surgery (1746 kcal/d; 95% CI, 1554 to 1937 kcal/d), followed by those with normal weight (1943 kcal/d; 95% CI, 1873 to 2013 kcal/d) and those eligible for bariatric surgery (2040 kcal/d; 1953 to 2128 kcal/d).In this cross-sectional study, individuals who underwent bariatric surgery had beneficial lifestyle patterns compared with those eligible for surgery; however, these improvements seemed suboptimal based on the current guidelines. Efforts are needed to incorporate benefits of physical activity and a healthy, balanced diet in postbariatric care.
Disease monitoring using lung function trajectory in lymphangioleiomyomatosis: assessment in two national cohorts
Authors: Jan Johnson, Iain Stewart, Simon R Johnson
Journal: Thorax (2022)

Study question In lymphangioleiomyomatosis, airflow obstruction and impairment of gas transfer progress at variable rates and serial lung function is recommended for disease monitoring. As these measurements are variable, recognising subjects needing treatment can be difficult. We used two prospective national cohorts to study change over time and variation in FEV 1 to inform clinical decision making. Patients and methods Clinical and lung function data for 141 UK and 148 American subjects were studied. Multilevel mixed effects modelling, route mean square analysis of errors and Bland-Altman analysis were used to analyse variability in lung function over time. Results At baseline assessment, DL CO was reduced to a greater degree than FEV 1 . In untreated patients, FEV 1 and DL CO declined at proportionately similar rates independent of initial lung function. In mechanistic target of rapamycin (mTOR) inhibitor treated patients, FEV 1 stabilised but DL CO continued to decline. FEV 1 /DL CO per cent predicted ratio was 1.37 (0.43) at baseline and increased to 1.41 (0.50) after 42 (24) months (p=0.0002). At least five measurements were required before &gt;70% of individuals had estimates of rate of FEV 1 loss within 50 mL/year and DL CO loss within 0.1 mmol/min/kPa/year of the final values. Conclusions While FEV 1 and DL CO fall proportionately in most, in early disease and during mTOR inhibitor treatment, DL CO should also be monitored as it may fall independent of FEV 1 . Since at least five observations over many months are required to make confident estimates of FEV 1 and DL CO trajectories, new strategies are needed to measure disease activity and target early treatment appropriately.
Abstract 363: Intracellular redox milieu regulates Mcl-1 and decreases overall mitochondrial priming in hematopoietic cancers
Authors: Jolin Xiao Lai, Stephen Jun Chong, Matthew Davids, Shazib Pervaiz
Journal: Cancer Research (2022)

Abstract Background: The dichotomy of redox signaling in cancer cell fate decisions has emerged as a topic of importance over the years. In particular, our group has highlighted the role of superoxide (O2 .-)-mediated signaling in the acquisition of drug resistance and cancer survival. Mechanistically, this involves post-translational modification of proteins involved in oncogenic signaling, such as c-Myc and NF-κB, as well as apoptosis resistance like Bcl-2 at the serine 70 phosphorylation site. Here we present evidence that O2 .--mediated signaling stabilizes anti-apoptotic protein Mcl-1, a commonly amplified gene in human cancers and is implicated in resistance to venetoclax, the Bcl-2 specific BH3 mimetic. Methods: Intracellular O2 .- levels was increased either pharmacologically or by siRNA mediated knockdown of SOD1 in MOLM14, RPMI8226, OCI-AML3 hematopoietic cell lines. Cell viability and apoptosis were assessed by MTT and Annexin V/DAPI staining. Protein expression was determined by Western blot analysis. BH3 profiling of patient-derived CLL cells was used to assess mitochondrial priming. Results: Elevated O2 .- levels increased Mcl-1 stability through Thr163 phosphorylation of Mcl-1, which in turn reduced ubiquitination-dependent degradation. Furthemore, venetoclax resistant cells possessed higher O2 .- levels and increase in intracellular O2 .- levels promoted resistance to Mcl-1 inhibitor, S63845 through increased binding between Mcl-1 and pro-apoptotic proteins NOXA and Bak. Contrarily, scavenging of O2 .- re-sensitized venetoclax-resistant leukemia cells to venetoclax. Importantly, BH3 profiling revealed that increase in intracellular O2 .- levels decreased overall mitochondrial priming in primary CLL cells by promoting sequestration of pro-apoptotic proteins that specifically target Mcl-1. Conclusion: Oncogenic activity of O2 .- is mediated by increased Mcl-1 stability through Thr163 phosphorylation, which resulted in a reduction in overall mitochondrial priming and increased binding of Mcl-1 to NOXA and Bak. Scavenging O2 .- reduces Mcl-1 levels and sensitizes resistant cells to venetoclax-induced apoptosis thereby demonstrating that manipulation of the redox microenvironment could be a potential vulnerability to be exploited in venetoclax resistant cancers Citation Format: Jolin Xiao Lai, Stephen Jun Chong, Matthew Davids, Shazib Pervaiz. Intracellular redox milieu regulates Mcl-1 and decreases overall mitochondrial priming in hematopoietic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 363.
Abstract 2338: Bioluminescent assays for measuringthemetabolic state of cancer and immune cells
Authors: Maggie Bach, Donna Leippe, Natasha Karassina, Michael Valley, James Cali, Jolanta Vidugiriene
Journal: Cancer Research (2022)

Abstract In the tumor microenvironment, cancer and immune cells compete for limited nutrients and both must undergo complex metabolic changes to support their function. To better understand the underlying mechanisms of tumor growth, metastasis and adaptation, a comprehensive analysis of metabolic pathways is needed. Success of such studies requires rapid and reliable approaches for monitoring key metabolic pathways, including glycolysis, the pentose phosphate pathway, fatty acid metabolism, amino acid metabolism and TCA cycle. Due to its inherent robustness, sensitivity and broad dynamic range, bioluminescence detection provides an attractive opportunity for developing such assays. Here, we implement a panel of bioluminescent metabolite assays (glucose, lactate, glutamine/glutamate, triglyceride/glycerol, cholesterol esters/cholesterol) to investigate the metabolic state of immune and cancer cells. We demonstrate flexibility of the assays in various volumes (96-, 384- well plates), sample types (2D, 3D cultures), automation platforms, and workflows, including detecting multiple metabolites in the same sample and monitoring metabolite changes over time by assaying multiple samples. We validate the performance of the assays by using metabolic pathway-specific inhibitors and demonstrating the utility of the assays as early indicators of cytotoxic T-cell activation. Finally, since metabolism is a dynamic process guided by fuel availability, we show the importance of medium composition when designing studies and suggest guidance for future work. In conclusion, understanding the crosstalk between tumor cells and their microenvironment is required for next-generation drug development. Bioluminescent metabolite assays provide the sensitivity, throughput and robustness required for rapid evaluation of changes in major metabolic pathways and are well suited for novel inhibitor screening and drug development. Citation Format: Maggie Bach, Donna Leippe, Natasha Karassina, Michael Valley, James Cali, Jolanta Vidugiriene. Bioluminescent assays for measuringthemetabolic state of cancer and immune cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2338.
Analysis of Lung Cancer Screening by Race After USPSTF Expansion of Screening Eligibility in 2021
Authors: Christine S. Shusted, Nathaniel R. Evans, Gregory C. Kane, Hee-Soon Juon, Julie A. Barta
Journal: JAMA Network Open (2022)

Registry.This group was divided into a USPSTF 2013-eligible cohort (age Ն55 years and Ն30 packyears, and quit <15 years ago) vs a USPSTF 2021-eligible cohort (age 50-54 years or 20-29 packyears, and quit <15 years ago).Race, ethnicity, and gender were determined through self-report.For the purposes of this study examining race, race was recoded to African American, White, and other, which included individuals who identified as Alaskan Native or American Indian, Asian, Native Hawaiian or Pacific Islander, and more than 1 race.An historical cohort from the same 9-month period in 2019 was identified for additional comparison.Descriptive statistics, independent t tests, and χ 2 tests were performed using a P < .05significance threshold.Statistical analyses were 2-sided and conducted using SPSS statistical software version 26 (IBM) from December 13 to 16, 2021.
Abstract 5746: Analysis of molecular characteristics of gliomas harboring gene fusions
Authors: Jidong Wang, Yushuai Han, Weiran Wang, Tonghui Ma
Journal: Cancer Research (2022)

Abstract Background: Genotyping plays an important role in tumor diagnosis and prognosis. The 2016 central nervous system (CNS) WHO added molecular parameters to classify CNS tumors on the basis of routine histological features, but the characteristics of gene fusion variations have not been clarified in CNS tumors. Methods: In order to identify the characteristics of gene fusions in Chinese patients with CNS malignant tumors, we retrospectively analyzed the next-generation sequencing data of 234 patients (pts) with gene fusions. Results: According to WHO classification of CNS tumor, 121 pts (51.7%) were low-grade gliomas (LGG, grade I, II), and 113 pts (48.3%) were high-grade gliomas (HGG, grade III, IV). The age of pts with LGG (14.1 ± 16.1) was significantly lower than HGG pts (50.2 ± 17.4) (P&amp;lt;0.0001). There was no significant gender difference between them (P = 0.161). In the fusion map of pts with LGG, gene fusions of KIAA1549-BRAF (n=82, 67.7%) and FGFR3-TACC3 (n=7, 5.8%) occurred frequently. Meanwhile, there were 5.7% pts carrying BRAF fusions with other partners, and some other sporadic fusions. Among HGG cases, the most frequent gene fusion was FGFR3-TACC3 (n=36, 31.9%), followed by fusions in EGFR (n=22, 19.5%), MET (n=16, 14.2%), BRAF (n=8, 7.1%), ROS1 (n=5, 4.4%), and other sporadic genes. It can be seen that gene fusion characteristics varied from gliomas with different malignant degrees. KIAA1549-BRAF fusion tended to occur in LGG (67.7% vs. 2.7%, P &amp;lt; 0.0001) than HGG, and FGFR3-TACC3 tended to occur in HGG ( 31.9% vs. 5.8%, P&amp;lt; 0.0001) than LGG. In addition, FGFR3-TACC3 fusion pts were exclusive with IDH1/2 mutations, but tended to be co-mutate with TERT promoter variants (P&amp;lt;0.0001). IDH-mutation-positive glioma usually exhibit a better clinical result, while TERT promoter-mutated glioma predicts a poor outcome. We also found that 75% (12/16) of MET fusion-positive gliomas pts had TP53 co-coexisting and 56.3% (9/16) of MET fusion-positive gliomas pts co-occurred with MET amplification, while only 0.9% (1/105) of pts harboring other fusions were MET amplification positive. Meanwhile, 95.0% (21/22) of EGFR fusion-positive pts co-occurred with EGFR amplification. Conclusion: By comprehensively analyzing the gene fusion map of Chinese patients with gliomas, we found the gene fusion characteristics of LGG differed from that of HGG. These fusion features may be important molecular information for judging the grade of malignancy and prognosis of patients. Citation Format: Jidong Wang, Yushuai Han, Weiran Wang, Tonghui Ma. Analysis of molecular characteristics of gliomas harboring gene fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5746.